Exogenously triggered controlled release materials and uses thereof

Abstract

The disclosure provides cross-linked materials that include multivalent cross-linking agents that bind an exogenous target molecule; and conjugates that include two or more separate affinity ligands bound to a conjugate framework, wherein the two or more affinity ligands compete with the exogenous target molecule for binding with the cross-linking agents and wherein conjugates are cross-linked within the material as a result of non-covalent interactions between cross-linking agents and affinity ligands on different conjugates. The conjugates also include a drug.

We claim: 
     
       1. A cross-linked material comprising:
 multivalent cross-linking agents that bind an exogenous target molecule; and 
 conjugates that include a drug and two or more separate affinity ligands bound to a conjugate framework, wherein the two or more affinity ligands compete with the exogenous target molecule for binding with the cross-linking agents and wherein conjugates are cross-linked within the material as a result of non-covalent interactions between cross-linking agents and affinity ligands on different conjugates, wherein the conjugate is of the general formula: 
 
       
         
           
           
               
               
           
         
         wherein: 
         each occurrence of 
       
       
         
           
           
               
               
           
         
          represents a potential branch within the conjugate; 
         each occurrence of 
       
       
         
           
           
               
               
           
         
          represents a potential branch within the conjugate; 
         each occurrence of 
       
       
         
           
           
               
               
           
         
          is independently a covalent bond, a carbon atom, a 
         heteroatom, or an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic; 
         each occurrence of T is independently a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C 1-30  hydrocarbon chain wherein one or more methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, —SO 2 N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group; 
         each occurrence of R is independently hydrogen, a suitable protecting group, or an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety; 
         —B is-T-L B -X; each occurrence of X is independently an affinity ligand; 
         each occurrence of L B  is independently a covalent bond or a group derived from the covalent conjugation of a T with an X; 
         -D is -T-L D -W; each occurrence of W is independently a drug; each occurrence of L D  is independently a covalent bond or a group derived from the 
         covalent conjugation of a T with a W; 
         k is an integer from 2 to 1 I, inclusive, defining at least two k-branches within the conjugate; 
         q is an integer from 1 to 4, inclusive; k+q is an integer from 3 to 12, inclusive; each occurrence of p is independently an integer from 1 to 5, inclusive; and each occurrence of n is independently an integer from 0 to 5, inclusive; and each occurrence of m is independently an integer from 1 to 5, inclusive; and each occurrence of v is independently an integer from 0 to 5, inclusive, with the 
         proviso that within each k-branch at least one occurrence of n is ≧1 and at least one occurrence of v is ≧1. 
       
     
     
       2. The material of  claim 1 , wherein the exogenous target molecule includes a saccharide. 
     
     
       3. The material of  claim 2 , wherein the exogenous target molecule is α-methyl-mannose. 
     
     
       4. The material of  claim 1 , wherein the affinity ligands of the conjugates include a saccharide selected from glucose, mannose, glucosamine, mannosamine, methylglucose, methylmannose, ethylglucose, and ethylmannose. 
     
     
       5. The material of  claim 1 , wherein the affinity ligands of the conjugates include a bimmanose or trimannose. 
     
     
       6. The material of  claim 1 , wherein the affinity ligands of the conjugates include aminoethylglucose (AEG), aminoethylmannose (AEM), aminoethylbimannose (AEBM) or aminoethyltrimannose (AETM). 
     
     
       7. The material of  claim 1 , wherein the multivalent cross-linking agents include a lectin. 
     
     
       8. The material of  claim 7 , wherein the lectins are covalently bonded to a recognition element, wherein the recognition element competes with the exogenous target molecule and affinity ligands of the conjugate for binding to the lectin, and the lectin has a higher affinity for the affinity ligands of the conjugate than for the recognition element. 
     
     
       9. The material of  claim 8 , wherein the exogenous target molecule is a saccharide and both the affinity ligands of the conjugate and the recognition element include a saccharide. 
     
     
       10. The material of  claim 1 , wherein the multivalent cross-linking agents include a peptide aptamer. 
     
     
       11. The material of  claim 1 , wherein the multivalent cross-linking agents include a polynucleotide aptamer. 
     
     
       12. The material of  claim 1 , wherein the drug is an insulin molecule. 
     
     
       13. A method comprising administering a material of  claim 1  to a patient and subsequently administering a triggering amount of the exogenous target molecule to the patient.